Transcranial focused ultrasound stimulation enhances semantic memory by modulating brain morphology, neurochemistry and neural dynamics

JeYoung Jung, Cyril Atkinson-Clement, Marcus Kaiser, Matthew A. Lambon Ralph

Nature Communications 2026, 17 · 10.1038/s41467-026-69579-7

human healthyhealthyfmriother mribehaviour

Abstract

The ventromedial anterior temporal lobe (ATL) is a core transmodal hub for semantic memory, yet non-invasive modulation of this region has remained challenging. Transcranial ultrasound stimulation (TUS) offers high spatial precision suitable for deep brain targets. In this study, we investigated whether theta-burst TUS (tbTUS) to the ventromedial ATL enhances semantic memory, using a multimodal neuroimaging approach-magnetic resonance spectroscopy (MRS), functional MRI (fMRI), and voxel-based morphometry (VBM). Compared to control stimulation, tbTUS improved semantic task performance. MRS showed decreased GABA and increased Glx, reflecting shifts in excitation-inhibition balance, alongside increases in NAA, creatine and choline, suggesting enhanced neuronal metabolism. fMRI demonstrated reduced ATL activity during semantic processing and strengthened effective connectivity across the semantic network. VBM revealed increased ATL grey matter volume. These findings provide convergent evidence that tbTUS modulates neurochemistry, functional dynamics, and brain morphology to enhance semantic memory, highlighting its neurorehabilitation potential.

Abstract via europepmc.

Specieshuman

Subjects23 participants

Sessions per subject2

Randomisednot reported

Blindingsingle

Sham / controlactive control site

Auditory controlmatched device sound, post hoc check

Readout timingoffline

Anaesthesianot applicable

Readoutsfmri, other mri, behaviour — Semantic association task and pattern-matching control task (accuracy, reaction time); GABA-edited MEGA-PRESS MRS (GABA+, Glx, NAA, choline, total creatine); voxel-based morphometry (grey matter volume); dynamic causal modelling of effective connectivity; post-study aversive-effects questionnaire

Direction of effectexcitatoryATL tbTUS decreased GABA+ and increased Glx (increased excitation-inhibition balance) and increased NAA, choline and total creatine relative to control (ventricle) stimulation; it decreased task-induced BOLD activity in the ATL, IFG and pMTG, increased grey matter volume in the ventromedial ATL, increased intrinsic effective connectivity across the semantic network, and improved semantic task accuracy.

Adverse eventsnone observedNo participants reported experiencing any discomfort during the experiment. The transcranial mechanical index (MItc; max = 1.33) and temperature rise (max at target=0.567 °C; max at tissue = 2.88 °C: max at skull = 4.69 °C) for both regions remained below the safety limits recommended by the United States Food and Drug Administration (US FDA).

Exposures

Exposure 1: tbTUS to the left ventromedial anterior temporal lobe (ATL)

Target: temporal pole — “left ventromedial anterior temporal lobe (ATL)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · CTX-500-4CH transducer with NeuroFUS PRO TPO-203 system ✓

Pulse timing
Waveform	theta burst
Fundamental frequency (kHz)	500	✓✓✓
Pulse duration (ms)	20	✓✓✓
Pulse repetition frequency (Hz)	5	✓✓✓
Duty cycle (%)	10pulse duration × PRF gives 10%	✓✓✓
Sonication duration (s)	80	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	not reported
Free-field Isppa (W/cm²)	not reported	⚑
Free-field Ispta (W/cm²)	not reported
In-situ estimate	simulationmean or range across subjects
In-situ pressure (kPa)	578.2	✓✓✓
In-situ Isppa (W/cm²)	11.46	✓✓✓
In-situ Ispta (W/cm²)	not reported
Isppa, domain unspecified (W/cm²)	54.51	✓✓✓

Protocol, in the paper’s words

Participants completed three sessions at least 5 days apart, counterbalanced across participants: session 1 acquired a T1-weighted MRI; sessions 2 and 3 applied tbTUS to either the left ventromedial ATL (active) or the left lateral ventricle (control), each followed by a semantic association task, a pattern-matching control task and MRS/fMRI/VBM scanning. Pulse repetition interval was 200 ms; steering depth was variable (ATL = 5.31 +/- 0.72 cm).

Flags from extraction

randomised — Paper states stimulation order was 'counterbalanced across participants' but never uses the word randomised.
exposures[0].free_field.isppa_w_cm2 — The 54.51 W/cm² ISPPA is given alongside the theta-burst protocol parameters (a device output specification) rather than explicitly labelled as a free-field/water measurement; placed here as the most likely domain, distinct from the simulated in-situ ISPPA reported separately.
exposures[0].target.terms — The paper's target is the 'ventromedial anterior temporal lobe (ATL)', which has no exact match in the target vocabulary; mapped to the closest listed term, temporal_pole.